Field of the Invention
The present application relates to systems and methods for enhancing the efficacy of various aspects of stem cell therapy. Several embodiments are directed to enhancing one or more of the isolation, proliferation, delivery, engraftment, differentiation, or function of stem cells. Several embodiments are directed to enhancing neurologic function in individuals having a loss of one or more neurologic functions, including but not limited to, motor function, cognitive function, including that resulting from injury, neurological disorders, normal age-related degeneration, etc. Other embodiments are directed to improving the viability or culturability of stem cells to be used in stem cell therapy or research.
Description of the Related Art
The scope of human disease that involves loss of or damage to cells is vast and includes, but is not limited to, cancers, ocular disease, neurodegenerative disease, endocrine diseases, and cardiovascular disease. The result of these diseases is typically some degree of loss of function of particular cells, and possibly an entire organ. This may lead to compromised quality of life, disability, or death. Injury or trauma to these cells or organs may yield similar effects.
Cell therapy involves the use of cells, and in some cases fetal, umbilical cord, placenta-derived, adult, induced pluripotent, or human embryonic stem cells and/or their partially or fully differentiated cellular derivatives to treat diseased or damaged tissues via replacement or regeneration. It is rapidly coming to the forefront of technologies that are poised to treat many diseases, in particular those that affect individuals who are non-responsive to traditional pharmacologic therapies. In some cases, cell therapy may be used prior to, or in response to, a therapy that itself induces damage to cells or tissues.
By way of example, bone marrow contains hematopoietic stem cells (HSC), which are precursor cells not dedicated to any particular blood cell lineage. Upon stimulation by particular cytokines the HSC may become committed to differentiating into cells of a particular lineage. Neutrophils, which are the predominant circulating white blood cells and account for nearly 70% of the total white cell count (normal range of 4×109 to 11×109 white blood cells/L of blood), are formed when HSC become committed to the granulocyte and/or macrophage lineage. Granulocyte colony-stimulating factor (G-CSF) is one example of a molecule that can induce the HSC to commit to forming neutrophils.
G-CSF (e.g., filgrastim, NEUPOGEN® by Amgen) is a cytokine produced by vascular endothelium and multiple types of immune cells. A G-CSF receptor (G-CSF-R) is present on HSC in the bone marrow. Upon binding to the G-CSF-R, G-CSF stimulates the proliferation of HSC and their differentiation into mature granulocytes, such as neutrophils. G-CSF is also a potent inducer of HSC mobilization and differentiation from the bone marrow into the bloodstream. G-CSF exists naturally, and synthetic forms have been also been developed for clinical use. Other hematopoietic stem cell stimulator/mobilizers are also available, such as Plerixafor (AMD3100, MOBOZIL® by Genzyme Corporation), a CXCR4 alpha-chemokine receptor modulator, that functions to stimulate the HSCs from the bone marrow to the periphery. Synergy between Plerixafor and G-CSF is possible. Granulocyte-macrophage colony stimulating factor (GM-CSF) is another cytokine that can promote differentiation of HSCs into neutrophils.
In normal humans, approximately one hundred billion neutrophils are produced daily and function as the primary defense against bacterial infections. Inactive neutrophils circulate in the blood stream with a half-life of about 12 hours. When activated, the circulating neutrophils are recruited to infected or inflamed tissues where they can internalize and kill a variety of microbes. Active neutrophils survive for approximately 1-2 days in the tissue and serve to prevent or reduce the likelihood of a large scale infection.
After their functional life-span has elapsed, neutrophils are typically destroyed by apoptosis, a sort of pre-programmed cell death. Circulating neutrophils counts are a result of the balance of neutrophil production and death. Neutropenia is a hematological disorder characterized by an abnormally low number of neutrophils (neutrophil granulocyte count below 0.5×109/litre). NNeutropenia can result from either decreased production or accelerated destruction of neutrophils. Neutropenic individuals are more susceptible to infections, including bacterial, fungal, and parasitic infections, with effects ranging from simple fevers to life-threatening sepsis.
Alterations in neutrophil homeostasis may result from autoimmune or hereditary disorders, cancers, particularly those affecting the blood cells, such as Hodgkin's disease or Non-Hodgkin lymphomas, stress, such as from surgery or trauma, or medication, such as chemotherapeutic agents. Some medications may also have agranulocytosis as a side effect, such as, for example, antiepileptics, antithyroid drugs (carbimazole, methimazole, and propylthiouracil), antibiotics (penicillin, chloramphenicol and co-trimoxazole), cytotoxic drugs, gold, NSAIDs (indomethacin, naproxen, phenylbutazone), mebendazole, the antidepressant mirtazapine, and some antipsychotics (the atypical antipsychotic clozapine). Some conditions may cause impaired neutrophil function without necessarily decreasing the quantitative number of neutrophils. This can be attributable to certain medications, such as steroids, alcoholism, or conditions such as diabetes, end-stage liver or renal disease, or immune disorders such as HIV.
Hodgkin's disease (HD) is a lymphoma, a hematological cancer that originates from uncontrolled growth of a sub-type of white blood cells known as lymphocytes. Treatment for HD typically involves radiation therapy, chemotherapy, or a combination of the two. Non-Hodgkin lymphomas (NHLs) are those lymphomas that are not classified as HD. Numerous classes of NHLs exist and they vary greatly in their aggressiveness. Thus, therapy for NHLs is tailored to the particular classification, but generally involves combinations of chemotherapy, immunotherapy, and radiation therapy.
In a broad sense, cancer is the rapid, uncontrolled growth of cells. Most chemotherapeutic agents act by inhibiting cell division, effectively targeting the fast-dividing cancer cells. However, there is currently no known cancer cell specific marker that targets the chemotherapeutic agents to cancerous cells. As a result, many normal cells, such as rapidly produced blood cells like neutrophils can also be affected. In combination with additional damaging effects on bone marrow and the subsequent drop in white blood cell production, virtually all chemotherapeutic regimes can cause suppression of the immune system due to neutropenia. It is therefore evident that when the chemotherapy is targeted to blood cells, as in HD and NHLs, the risk of neutropenia is even greater.
While there is no ideal therapy for neutropenia, several approaches have evolved to address neutropenia in the cancer treatment setting. When doses of chemotherapy are relatively low, the bone marrow may remain viable and marginally functional. In these cases, G-CSF and/or administration of other agents concurrent with chemotherapy may be used to combat neutropenia through the increased production of neutrophils. However, when higher doses of chemotherapy are needed, G-CSF may be used prior to chemotherapy to stimulate proliferation of HSC, which can be harvested and later transplanted back into the patient. While these approaches have produced positive results, increasing production of HSC and neutrophils in cancer patients remain major hurdles.